Feedback control of total peripheral resistance (TPR) by the arterial and cardiopulmonary baroreflex systems is an important mechanism for arterial blood pressure (ABP) regulation. Traditional techniques for measuring the TPR baroreflex aim to quantify the open-loop gain value of one baroreflex system. While multiple regression analysis (MRA) can determine the closed-loop gain values of both systems, this analysis mandates a sophisticated experimental preparation in which both heart rate and blood volume are perturbed and has therefore received little attention. Thus, the integrated functioning of both TPR baroreflex systems remains poorly understood. Our hypothesis is that both TPR baroreflex systems may be distinctly quantified from only the information present in naturally occurring, beat-to-beat hemodynamic variations. While this subtle variability has been the focus of many baroreflex studies in the past, it has not been exploited specifically for the characterization of the TPR baroreflex. We have developed a mathematical algorithm to quantify the closed-loop gain values of each TPR baroreflex by analyzing only beat-to-beat measurements of ABP and cardiac output (CO). We have demonstrated the feasibility of the algorithm in a single animal and in a small set of humans in which ABP and CO were noninvasively measured. We propose further development and rigorous evaluation of the algorithm in chronic animal studies. Specific Aim 1 is to validate the TPR baroreflex gain values determined by the mathematical algorithm. We will study up to15 conscious dogs with atrio-ventricular (AV) block and instrumented for cardiac pacing and measurement of ABP, CO, and central venous pressure (CVP). This experimental preparation will allow us to compare the TPR baroreflex gain values determined by applying the algorithm to ABP and CO measured during AV sequential pacing with reference values established by applying MRA to ABP, CVP, and CO measured during a set of adjustments to ventricular rate and blood volume. Specific Aim 2 is to demonstrate that the TPR baroreflex gain values determined by the mathematical algorithm are valid under various baroreflex states. We will repeat the above protocol after the administration of drugs that alter baroreflex functioning. Successful achievement of these specific aims may ultimately lead to a practical technique that is routinely employed to advance the basic understanding of the TPR baroreflex in both humans and animals in health and disease. [unreadable] [unreadable] [unreadable] [unreadable]